Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection.
Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection.
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作者：
癌症研究正确且成功地集中在预防、早期检测和识别特定分子靶标上，这些分子靶标可将恶性细胞与邻近的良性细胞区分开来。然而，一个主要的临床挑战是如何减少晚期转移性癌症治疗期间强化放化疗引起的致命组织损伤。在这里，我们测试了成体干细胞的诱导是否可以修复放化疗引起的组织损伤并延长总体生存期。我们发现肠道干细胞 (ISC) 表达 Slit2 及其单跨膜细胞表面受体 Roundabout 1 (Robo1)。 Robo1 的部分基因缺失减少了肠干细胞 (ISC) 并导致绒毛萎缩，而 Slit2 转基因增加了 ISC 并引发绒毛肥大。在致死剂量的放化疗期间，给予短脉冲 R-spondin 1（Rspo1；一种 Wnt 激动剂）加 Slit2 可减少 ISC 损失，减轻肠道损伤并保护动物免于死亡，同时不会降低肿瘤对化疗的敏感性。因此，Rspo1 和 Slit2 可以作为治疗佐剂，增强宿主对激进放化疗的耐受性，从而根除转移性癌症。
Cancer research has been righteously and successfully focused on prevention, early detection and identification of specific molecular targets that distinguish the malignant cells from the neighboring benign cells. However, a major clinical challenge concerns how we can reduce lethal tissue injury caused by intensive chemoradiotherapy during treatment of late-staged metastatic cancers. Here we tested whether induction of adult stem cells repairs chemoradiation-induced tissue injury and prolongs overall survival. We found that intestinal stem cells (ISCs) expressed Slit2 and its single-span transmembrane cell-surface receptor Roundabout 1 (Robo1). Partial genetic deletion of Robo1 decreased intestinal stem cells (ISCs) and caused villus hypotrophy, whereas Slit2 transgene increased ISCs and triggered villus hypertrophy. During lethal dosages of chemoradiation, administering a short pulse of R-spondin 1 (Rspo1; a Wnt agonist) plus Slit2 reduced ISC loss, mitigated gut impairment and protected animals from death, without concomitantly decreasing tumor sensitivity to chemotherapy. Rspo1 and Slit2 may thus act as therapeutic adjuvants to enhance host tolerance to aggressive chemoradiotherapy for eradicating metastatic cancers.
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DOI：
10.1084/jem.20101559
发表时间：
2011-02-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Takashima S;Kadowaki M;Aoyama K;Koyama M;Oshima T;Tomizuka K;Akashi K;Teshima T
通讯作者：
Teshima T
影响因子：
64.8
作者：
Seshagiri, Somasekar;Stawiski, Eric W.;Durinck, Steffen;Modrusan, Zora;Storm, Elaine E.;Conboy, Caitlin B.;Chaudhuri, Subhra;Guan, Yinghui;Janakiraman, Vasantharajan;Jaiswal, Bijay S.;Guillory, Joseph;Ha, Connie;Dijkgraaf, Gerrit J. P.;Stinson, Jeremy;Gnad, Florian;Huntley, Melanie A.;Degenhardt, Jeremiah D.;Haverty, Peter M.;Bourgon, Richard;Wang, Weiru;Koeppen, Hartmut;Gentleman, Robert;Starr, Timothy K.;Zhang, Zemin;Largaespada, David A.;Wu, Thomas D.;de Sauvage, Frederic J.
通讯作者：
de Sauvage, Frederic J.
Slit2 通过肺部炎症期间 srGAP1 的差异表达来调节吸引性嗜酸性粒细胞和排斥性中性粒细胞趋化性
影响因子：
4.4
作者：
Ye, Bu-Qing;Geng, Zhen H.;Geng, Jian-Guo
通讯作者：
Geng, Jian-Guo
影响因子：
11.8
作者：
Grieshammer, U;Ma, L;Martin, GR
通讯作者：
Martin, GR
影响因子：
3.7
作者：
Booth, C;O'Shea, JA;Potten, CS
通讯作者：
Potten, CS